SL Fentanyl and Methadone- Are they friends or enemies? Pamela Mansfield MD CCFP Clinical Director of Palliative Care Moncton Area, Horizon Health Network Past President of the NBHPCA President of the Moncton Medical Staff Lecturer Dalhousie University April 25, 2013

Disclosure: Unrestricted educational grant

Learning Objectives At the end of the session the participant will: Be able to identify the various opioids available to treat pain Know the potencies of the different opioids Understand dosing of opioids Know the principles of breakthrough pain Know the medications available to treat breakthrough pain Name the unique properties of methadone and reason for its use Understand the specific toxicity unique to methadone and potential drug interactions Demonstrate the steps for starting and rotating patients to methadone

At the end of the day the participant will be able to: Identify my husband, Nathanael Anderson

Opioids 101 Opioids: Originally derived from opium Natural and synthetic Narcotic (Greek work for stupor) – dependence /addiction

Classification of Opioid Receptor Sites Adapted from Medical care of the Dying, 4th Ed. Effect Mu (OP3) Kappa (OP2) Delta(OP1) Pain Analgesia Respiratory rate Depression Heart Rate Bradycardia GI Nausea Reduced motility Constipation Affect Sedation Indifference ?euphoria Psychotomimetic Dysphoria

Opioids 101 Different Opioids: Codeine Butrans Tramadol Morphine Nucynta Oxycodone Hydromorphone Fentanyl Methadone

Opioid Equivalency DRUG PO DOSE SC/IV DOSE FORM COMMENTS Morphine 10mg Tab (IR,SR) Inj Supp Codeine 100mg 50mg Tramadol N/A Tab (IR, SR) Oxycodone Tab (IR,SR) Hydromorphone 2mg 1mg Methadone Special PO/PR/SL Duration & half-life increase with repeated use (cumulative effect) Fentanyl 25 mcg/hr ~ 100mg PO morphine/ 24h Roughly 100mcg/h = morphine 4 mg/h iv SR Patch IR SL Change SR patch q 72 hours Reservoir takes 12 hours to build

Adverse Effects & Management Sedation/Drowsiness Tend to clear in a few days Ritalin? Confusion/Delirium Associated with sedation Usually occurs in titration phase Hallucinations/Dysphoria Reassurance No specific TX – antipsychotics?

Adverse Effects & Management Dry mouth: common - Increase fluids, suck on candy/ice chips Puritis – histamine release; Nonsedating antihistamines Nausea/Vomiting/Dyspepsia Caused by stimulation of the chemoreceptor trigger zone Occurs in 50-70% of pts Usually resolves in a few days Antiemetics

Adverse Effects & Management Respiratory depression*****see methadone slide! In the presence of ongoing pain: RARE Occurs primarily when opioid-naive pts are initiated at high doses, or when dosage increases are made too rapidly Naloxone only if severe (0.1-0.2 mg IV q 1-2 min until alert; only lasts 10-15 min) Physical Dependence Withdrawal if therapy stopped abruptly Myoclonus TX with benzo, or anticonvulsant

Adverse Effects & Management Will the S/Es go away? Tolerance develops to the respiratory depression, nausea, vomiting and sedation… …but NOT constipation! http://www.youtube.com/watch?v=HEpwXiRoBOs

Principles of Dosing Better to schedule medication instead of waiting for pain – otherwise just chasing pain! Short acting (intermediate release) – q 4h Steady state plasma level ~ 1 day Long acting (sustained release) – q12 h Stead state plasma level within 2-4 days

What is Breakthrough Pain? 1st defined in 1990 by Portenoy and Hagen as “transient increases in pain in a cancer patient who has stable, persistent pain treated with opioids” episodic/transient/breakers/inbetween/ interd0se International Association of the Study of Pain - “a transitory flare of pain that occurs on the background of relatively controlled baseline pain”

What is Breakthrough Pain? An acute episode of pain superimposed on constant/ongoing pain Frequency and duration varies considerably from patient to patient Few seconds – couple of hours

Typical Episode of BT Cancer Pain BTcP refers to the pain flares that occur beyond the baseline persistent pain

Uncontrolled Baseline Pain vs BT Pain BTcP must be distinguished from uncontrolled background pain, for successful treatment 1. Portenoy RK and Hagen NA. Prim Care Cancer 1991:27–33. 2. Bennett D et al. P&T 2005;30:296–301.

Not BT Pain End of dose failure Baseline/Persistent Pain Incident Pain – but also only lasts for a short time and predictable, and baseline pain is controlled

What is Breakthrough Pain? A BT dose is an additional dose – it does not replace/delay administration of next regular dose

Impact of Breakthrough Pain Patients with BT pain have higher levels of: Background pain Peak pain Depression Anxiety Functional impairment BT pain has a significant negative effect on quality of life

Breakthroughs GROT: 10% of total daily dose given q1h (po) or q30min s/c Or ½ of q4h dose If pain uncontrolled incr dose: 25-50% mild-moderate pain, 50-100% for severe to uncontrolled pain Or at least equal to amts of BTs used

BT Medication Same opioid as long acting opioid – reaches peak effect in 30 min (sc) or 1 hour (po), lasts 4 hours Fentanyl/Sufentanyl SL or SC – faster onset, inconvienent delivery

What we want…..

BT Medication New option – ABSTRAL

Characteristics of fentanyl citrate Lipophilic opioid analgesic with a potency 100 times that of morphine1 The most lipophilic of the clinically available immediate-release opioids2 Well suited to oral transmucosaldelivery2 Quickly crosses cellular barriers, providing broad tissue distribution and rapid onset of action3 Oral transmucosal fentanyl citrate (OTFC) The first rapid-onset opioid to be approved for the treatment of BTcP4 Recommended by the European Association of Palliative Care5 1. Abstral™ Product Monograph. 2. Bennett D et al. P&T 2005;30:354–361. 3. Coluzzi PH. Am J Hosp Palliat Care 1998;15:13–22. 4. Actiq® Cephalon 2009 5. Hanks GW et al. Br J Cancer 2001;84:587–593

Fentanyl Citrate

Oral transmucosal administration Convenient and easy to use1 Takes advantage of characteristics of the oral mucosa that facilitate rapid absorption:2 large surface area high permeability high vascularity uniform temperature Associated with high bioavailability, due to avoidance of first-pass metabolism3 1. Zeppetella G. Palliat Med 2001;15:323–328. 2. Simmonds MA. Oncology 1999;13:1103–1108. 3. Weinberg DS et al. Clin Pharmacol Ther 1988:44:335–342

Abstral Indication For the management of breakthrough pain in cancer patients who are already receiving, and who are tolerant to, opioid therapy* for their persistent baseline cancer pain Adults 18 years of age or older * Patients taking for one week or longer (≥), at least: 60 mg oral morphine/day; 25 mcg transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; or an equianalgesic dose of another opioid for 1 week or longer.

Abstral Contraindications Non-opioid-tolerant patients The management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room Patients with severe respiratory depression or severe obstructive pulmonary conditions Patients with known sensitivity or intolerance to fentanyl products

Appropriate Patient Selection for Abstral Patient must have persistent baseline pain Baseline pain must be adequately controlled Patient also experiences transient episodes of moderate-to-severe pain

Abstral Pharmacological characteristics Fentanyl citrate has a potency approximately 100 times that of morphine1 Overall bioavailability of Abstral is estimated to be 54% mainly through the oral mucosa1 Pharmacokinetics of Abstral display dose proportionality over the dose range of 100–800 µg, with single and multiple dosing1,2 1. Abstral™ Product Monograph 2011 2. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85

Absorption of Abstral across the oral mucosa Abstral is formulated as rapidly disintegrating sublingual tablets1

Abstral pharmacokinetic profile during the first 60 minutes

Efficacy of Abstral in patients with cancer: Phase III primary endpoint Abstral gave rise to significant improvements in pain intensity versus placebo: Mean summed pain intensity difference was significantly greater with Abstral than placebo at both 30 and 60 minutes (p≤0.0005)

Efficacy of Abstral in patients with cancer: Phase III Secondary endpoint Greater improvements in pain intensity difference were observed with Abstral versus placebo from 10 minutes post-dose Significant differences were maintained throughout the 60-minute assessment period (Abstral versus placebo, p≤0.0055) More patients reported ≥30% reduction in pain intensity with Abstral than with placebo (p<0.0001)

Dosage and administration To administer Abstral, one tablet is placed under the tongue at the deepest part of the sublingual cavity, where it is allowed to dissolve completely Chewing, sucking or swallowing could result in reduced absorption and low plasma concentrations of fentanyl Abstral tablets are available in six dosing strengths:

Recommended titration schedule The initial dose of Abstral used must be 100 µg Abstral dosing for a subsequent episode should be separated by at least 2 hours No more than four doses per day

Long-term safety of Abstral 1. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85. 2. Nalamachu S et al. Curr Med Res Opin Vol.27,No.3,2011,519–530

Long-term safety of Abstral: adverse events 1. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85. 2. Nalamachu S et al. Curr Med Res Opin Vol.27,No.3,2011,519–530

Reminder: Key Safety Messages Must not be used in opioid non-tolerant adult cancer patients Abstral – Starting dose is 100mcg S/L; titrate by 100mcg until 400mcg, then tirate by 200mcg (max dose = 800mcg) separated by 2h; max 4 doses/day ABSTRAL contains fentanyl, a controlled substance with potential for being abused and sought after by drug abusers/people with addiction disorders

Reminder: Key Safety Messages Fentanyl products, which are designed to manage breakthrough pain, should not be used in patients who are receiving partial opioid agonists such as buprenorphine or agents with some opioid effects such as tramadol, as the safety of their concomitant use has not been established Patients and caregivers must follow proper storage, handling and disposal guidelines

BTP Conclusion Uncontrolled Baseline Pain does not equal Breakthrough Pain Breakthrough pain needs to be treated to have good overall pain control Usual choice of breakthrough is 10% of current 24hr opioid dose ABSTRAL are new options: has demonstrated rapid onset of action Easy-to-administer S/L tab Demonstrated favourable safety profile when used in adult opioid-tolerant cancer patients AEs as expected for opioid medications

Questions?

What is Methadone? Synthetic opioid Similar in binding to mu, kappa receptors; delta? Unique from other opioids is NMDA receptor antagonist, and 5-HT/NE neuronal reuptake Invented in Germany during WWII 1960s - Used to treat heroin addiction 1980s – renewal of interest for treating pain Problem? Variable opioid conversion ratio, long half-life, and drug interactions make it a scary drug!

Methadone is Lipophilic: Good: GI tract and cutaneous absorption Bad: accumulation in tissues and increased protein binding → prolonged retention Onset of action 30min, peak effect in 3-4 hours, half-life 12-150 hours “rapid and extensive distribution phase followed by slow elimination phase”

Methadone Pharmacology During Initial Dosing Period (0 to 1 day) Free fraction in plasma Drug elimination B Analgesia A Majority of drug initially sequestered to tissue binding sites B Small quantity of methadone available

Methadone Pharmacology At Steady State (3 – 5 days +) Analgesia C Once the reservoir is full, subsequent doses available to plasma (leading to reduced requirement) D Increased dose fraction for analgesia E In steady state, equilibrium is maintained – in effect a slow-release reservoir

Methadone Elimination Eliminated mainly via liver metabolism and fecal excretion (renal minor) Renal and hepatic impairment do not affect methadone clearance No active metabolites

Methadone and Prolonged QT Mechanism not yet fully identified Significant QTc prolongation is defined as > 500 msec Risk factors include: low K+ or Mg+ (a side-effect of cisplatinum therapy), hx of CHF, bradycardia or baseline long QT, liver disease, concomitant disuse or use of medications, or a reduction in plasma protein levels which then increase methadone concentration QTc in females normal up to 460 msec and 440 msec in males A change of 40-60 msec from baseline or absolute value greater than 500 is considered significant

Methadone and Prolonged QT Suggested Guidelines: What are the goals of care? Do we “care” if the QT interval is prolonged? ECG if methadone dose > 300 mg/d Recheck with methadone dose increases Recheck if possible drug interaction that could increase effective dose If QT between 450-500 msec, consider increasing methadone with caution and ECG reassessment If QT > 500 msec, consider reducing dose of methadone

Methadone Dosing In addiction: OD For Pain: BID to TID, maybe QID? Conversion morphine to methadone: Morphine Equivalent Drug Dose – MEDD Anywhere from 2.5:1 to 15:1

Different MEDDs: Edmonton model: 10:1 methadone to morphine Milan model: 4:1 if 30-90 mg morphine 6:1 if 90-300 mg morphine 8:1 if > 300 mg morphine UK model: 10:1 if < 300 mg morphine a day > 300 mg morphine start with 30 mg/day in divided doses Palermo model: 5:1 (20%) of previous daily dose of morphine NS Cancer Centre: 10:1 if <500 mg morphine a day 20:1 if >500 mg morphine a day

Reasons for Rotating Opioids

Reasons for Rotating Opioids Inadequate Pain Relief Side Effects sedation, nausea/vomiting, confusion/delirium, dry mouth, dizziness, puritis, urinary retention, opioid-induced neurotoxicity, myoclonus, mood changes Dosage/Volume Lose route Tolerance

How to rotate opioids Calculate equivalent dose Reduce by 25-30% for incomplete cross tolerance at the receptors Stop new opioid and start new

Edmonton Model Occurs over three days Day 1: Decrease 30% of the morphine dose over 24 hours and replace it with methadone every 8 hours using a morphine:methadone 10:1 Breakthrough – use same med as before Day 2: If pain control good, decrease the original dose of morphine by another 30%; increase the dose of methadone only if the patient experiences moderate to severe pain Day 3: Discontinue the last 30% of the original morphine dose and maintain patient on regular methadone tid

Modified Morley-Makin Model Stop current opioid Calculate MEDD Use 10% of MEDD every 3 hours prn (10:1), not to exceed 30 mg/dose On day 6, divide the total dose of methadone given in the last 48 hours by 4 and use the dose q 12 h, or divide by 6 and use the dose q 8 h BTD is 10% of daily dose q3h prn

Cowboy Method Mansfield-Horton Model Stop opioid Start methadone at 5-10 mg tid depending on pain and previous opioid dose (10:1, max 30 – 45 mg/day) Increase every 3-5 days depending on pain Mild pain 25%, moderate pain 33%, severe pain 50-100% If opioid naive, start at 2.5 mg bid Use previous breakthrough dose, or once pain stable change to methadone for breakthrough (10% daily dose q 3 h prn)

Chicken Method Calculate the MEDD Decrease current opioid dose by 1/3, start 1/3 of calculated methadone target dose (bid or tid) Wait 3 days, decrease current opioid dose by another 1/3, increase methadone dose by 1/3 or best judgement Wait 3 more days, d/c old opioid dose, increase methadone to target dose or best judgement

Breakthroughs for other Opioids 10% of total daily dose or ½ of q4h dose, given po q1h prn, or s/c q 30 min prn If pain uncontrolled, increase dose: 25-50% mild-moderate pain 50-100% for severe to uncontrolled pain Or at least equal to amts of BTDs used

Breakthrough for Methadone 10% of total daily dose of previous opioid, or ½ of q4h dose, given po q1h prn, or s/c q 30 min prn OR: 10% of total daily methadone dose given po q 1h prn or q 3h prn, max 6 doses per day If pain uncontrolled increase dose: 25-50% for mild-moderate pain, 50-100% for severe to uncontrolled pain Or at least equal to amts of BTs used

Methadone Overdose? Sedation always proceeds respiratory depression Monitor for and concern if: Lack of response to tactile or vigorous stimuli RR < 10/min Systolic BP < 90 mmHg or 20% less than baseline O2 saturation levels occasionally helpful but can be falsely reassuring Consider in patients with history of sleep apnea, obesity or any condition which decreases ventilation capacity

Methadone Overdose Methadone Toxicity Treatment Nalaxone 0.1-0.2 mg q 2 min until respiratory rate > 8/min and O2 saturation > 90% Repeat q 20-30 min until patient stabilized. Because of methadone’s long half life, a naloxone infusion may be required following stabilization Start with 50 mcg naloxone (0.1 mcg/ml) per hour and titrate to effect

Potential methadone drug interactions There are 2 ways to cause an effect: 1. By starting a medication which will alter the metabolism, e.g.: Starting fluconazole or paroxetine may reduce clearance resulting in increased serum levels and sedation/toxicity Starting retonavir or dilantin may increase clearance resulting in decreased levels and may reduce analgesia or ppt withdrawal

Potential methadone drug interactions By stopping a medication which will alter the metabolism, e.g.: Stopping fluconazole or paroxetine may increase clearance resulting in decreased serum levels and reduced analgesia or withdrawal symptoms Stopping retonavir or dilantin may decrease clearance resulting in increased levels and may increase analgesia or cause sedation/toxicity

Potential methadone drug interactions CYP3A4 inhibitors – increase methadone levels CYP3A4 inducers – decrease methadone levels Fluconazole Rifampin Ketoconazole Phenytoin Fluoxetine* Phenobarbitol Norfluoxetine* Carbamazepine Fluvoxamine* Risperidone Paroxetine* Ritonavir Macrolide antibiotics Nevirapine Nifedipine Glucocorticoids Verapamil Fusidic acid Diltiazem Grapefruit juice Sertraline hydrochloride* Cimetidine Nafazedone* *Also inhibits CYP1A2 See cards

Case 1 Jackie, 52 yo female with metastatic breast ca to lung, liver, bone, and brain Major pain is in head Tried other adjuvants On 48 mg hydromorph contin bid now, BT hydromorphone 12 mg po q1h prn (taking 10/day) Still no difference in pain level!

Rotate to methadone

Case 1 Hydromorph contin 96 mg/day =~ 500 mg morphine/day 10:1 ratio for MEDD yields a methadone dose of 50 mg/day

Case 1 Method: BT dose:

Case 2 Sarah, 45 yo female with metastatic rectal ca Pain is rectum, radiating down legs Currently on hydromorphone 8 mg/h in CADD

Case 2 Rotate to methadone

Case 2 Hydromorphone 8 mg/h = 192 mg s/c hydromorphone/day Hydromorphone 192mg s/c = 384 hydromorphone po/day Hydromorphone 384 mg = 1920mg morphine 10:1 MEDD = 192 mg methadone/day

Case 2 Method: BT dose:

Case 3 Burt, 60 yo male with pancreatic ca Pain is epigastric, hard to describe Was on hydromorph contin 24 mg po bid, then rotated to Duragesic, and titrated up to Duragesic 150 ug/h Still using hydromorphone 12 mg po q 1 h prn and showing signs of neurotoxicity

Case 3 Rotate to methadone

Case 3 Duragesic 150 ug/hr = ~600mg morphine/day 10:1 ratio = 60 mg methadone

Case 3 Method: BT dose:

Case 4 Glenda, 65 yo female multiple myeloma Pain in back, admitted with nausea/vomiting, thought to be related to escalating morphine doses MS Contin 100 mg po bid

Case 4 Rotate to methadone

Case 4 MS Contin 200 mg/day, 10:1 ratio = Methadone 20 mg

Case 4 Method: BT dose:

Case 5 Harold, 62 yo male with multiple myeloma and post herpetic neuropathic pain in the occipital region – rates as 8/10 Not using opioids regularly, finds “they don’t work” On maximum dose gabapentin, as well as amitriptyline

Case 5 Start him on methadone

Case 5 Relatively opioid naïve Methadone starting dose?

Case 5 Method: BT dose:

Key Messages About Prescribing Methadone for Pain Titrate slowly to analgesic effect reduces risk of toxicity/sedation/respiratory arrest pain threshold is reached at lower doses than sedation threshold and respiratory-arrest threshold Avoid drug interactions via careful history

Key Messages About Prescribing Methadone for Pain Monitor closely for adverse effects and drug interactions ask about/investigate drug interactions at every visit Educate patients and include them as part of the care team being attentive to/reporting adverse effects and informing about other drugs being taken

Key Messages About Prescribing Methadone for Pain Methadone is a highly effective opioid for pain and can and should be used not just third line, but second and first line!

Questions?